Embolic microspheres

Abstract

Functionalized embolic microspheres may be employed as a platform for radiotherapy, for enabling loading multiple drugs with different physicochemical properties and / or different mechanisms of killing cancer cells. The functionalized embolic microspheres may be radiopaque for x-ray visibility or Magnetic Resonance imageability. In aspects, different functionalized embolic microspheres carrying different drugs and having different radiopaque compounds may provide distinct imageability for the different drug eluting microspheres.

Description

EMBOLIC MICROSPHERESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 617,675, filed January 4, 2024, which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE DISCLOSURE

[0003] Therapeutic transarterial embolization, including transarterial chemoembolization (TACE), has been used as loco-regional therapy treatment modality for various lesions for more than four decades. Direct and long-lasting visualization of embolic materials is important to control the extent and define the endpoints of embolization, identify nontarget embolization, as well as for post embolization follow up. Conventional iodinated contrast media technology has been applied in the field of therapeutic embolization. However, there are at least two major shortcomings with the use of iodinated contrast media: First, its potential toxicity and second, due to its small atomic number (Z=53), iodine is less effective at attenuating x-rays at energies higher than 50 keV. In clinical settings, images are frequently acquired at, for example, 80, 100, and 120 kVp. Accordingly, improved embolic microsphere technology is needed.BRIEF SUMMARY OF THE DISCLOSURE

[0004] In one aspect, a microsphere comprises at least one functionalized chemical structure covalently bonded thereto, the microsphere and functionalized chemical structure having the formula:wherein:represents the microsphere. Each R1may be independently selected fromNH2, NH3, OH, O, amine, alkoxy, alkyl, and aryl. Each R2is independently selected from 0 or OH; and n is greater than or equal to 1.

[0005] Additional aspects of the disclosure are as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 shows an example of a functionalized embolic microsphere platform derived from Oncozene Beads, which allows for the loading of anionic drug / s.

[0007] Figure 2 shows a functionalized embolic microsphere platform from Oncozene Beads (Embozene TANDEM), which allows including chelated radiopaque or radionuclide metal, M, wherein M can be Bi, Gd, Fe, or radionuclides (Holmium-166, Ho-166; Yttrium- 90, Y-90; Rhenium-188, Re-18) - see also Figures 4A and 5A. It also allows for the ionic binding of therapeutic agents.

[0008] Figure 3A shows the chemical formula of one example of a functionalized microsphere with iodine containing moiety.

[0009] Figure 3B is an scanning electron microscope (SEM) image of the functionalized microsphere of Figure 3A showing the intact spherecity of the product microsphere.

[0010] Figure 3C is an energy dispersive X-ray analysis (ED AX) image of iodine functionalized microsphere of Figure 3 A showing the iodine distribution on the microsphere.

[0011] Figure 3D is a micro-computed tomography (microCT) image, including HU value, of the functionalized microsphere of Figure 3 A showing x-ray visibility.

[0012] Figure 4A shows the chemical formula of one example of a functionalized microsphere chelated with a radiopaque metal M, wherein M is Bi.

[0013] Figure 4B is an SEM image of the functionalized microsphere of Figure 4A showing intact microsphericity of the product microsphere.

[0014] Figure 4C is an ED AX image of bismuth functionalized microsphere of Figure 4A showing the bismuth distribution on the microsphere.

[0015] Figure 4D is a microCT image, including HU value, of the functionalized microsphere of Figure 4A showing radi opacity of the product microshpere.

[0016] Figure 5A shows the chemical formula of one example of an embolic microsphere including chelated radionuclide metal, M, wherein M can be Holmium-166, Ho-166; Yttrium-90, Y-90; or Rhenium-188, Re-18.

[0017] Figure 5B shows the chemical formula of one example of a functionalized microsphere including radioactive yttrium-90.

[0018] Figure 6 shows the chemical formula of one example of a functionalized microsphere as a boron containing anticancer drug delivery system, including Capacitabine attached via the boron functional group.

[0019] Figure 7 shows a non-exhaustive group of anticancer drugs, including Capacitabine, that can be delivered via a functionalized microsphere boron-containing anticancer drug delivery system.

[0020] Figure 8 shows a schematic flow diagram of aspects of dual drug loading of a plurality of embolic microspheres.

[0021] Figure 9 shows aspects of dual drug loading of a functionalized embolic microsphere. As shown, the drug may be ionic in its form.

[0022] Figure 10 shows a functionalized embozene microsphere aspect showing dual drug loading. A drug can be cationic, interacting with an anionic portion of the microsphere, and / or a drug can be anionic, interacting with a cationic portion of the microsphere.

[0023] Figure 11 shows a schematic flow diagram for producing embolic microspheres having: (A) single drug loading capability; (B) dual drug loading but lacking radiopaque functionality; (C) dual drug loading including iodinated radiopaque functionality; and (D) dual loading including radiopaque or MR visible functionality from metals such as Bi, Gd, or Fe.

[0024] Figure 12 shows a chemical scheme for functionalization of an embozene microsphere 1 with Triamine group to produce microsphere 2.

[0025] Figure 13 shows a chemical scheme for functionalization of microsphere 2 with Triethylenetetramine-N,N,N',N'',N"',N'"-hexaacetic acid to produce microsphere 3.

[0026] Figure 14 shows a chemical scheme for radiopacification of microsphere 3 with an iodine moiety to produce microsphere 4.

[0027] Figure 15 shows chelation of bismuth on to microsphere 2 to produce microsphere 5.DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] In aspects, the disclosed systems and methods provide for the synthesis of imageable functionalized embolic microspheres using iodine, bismuth, lanthanides or other radiopacifiers.

[0029] The resulting CT imageable microspheres are capable of delivering multiple drugs on the same microsphere. The CT imageable microspheres are further capable of delivering multiple drugs in an independently imageable fashion, wherein a first functionalizedmicrosphere comprising a first radiopaque compound may be configured to deliver a mono or dual drug / s, and a second functionalized microsphere comprising a second radiopaque compound may be configured to deliver a mono or dual drug / s. Thus, the extent of embolization for each type of microsphere and each drug may be imaged.

[0030] Accordingly, the disclosed microspheres may function as a platform for radiotherapy or enabling loading multiple drugs with different physicochemical properties and mechanism of killing cancer cells as well as a radiopaque for x-ray visibility or Magnetic Resonance imageability with a potential for the treatment of liver cancer.

[0031] In aspects, an embolic microsphere has at least one functionalized chemical structure covalently bonded thereto, the functionalized chemical structure having the formula:wherein:represents the microsphere containing carboxylic functional groups; each R1is independently selected from NH2, NH3, OH, 0, amine, alkoxy, alkyl, and aryl; and each R2is independently selected from 0 or OH. In aspects each R1is independently ionically bonded to a therapeutic compound. In aspects, each R1is independently NH3 or 0. In aspects, n is greater than or equal to 1. In aspects, n may be less than 10, preferably less than 6, more preferably less than 3. In aspects, n may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In aspects each R1may have less than 20 carbons, preferably less than 10 carbons.

[0032] In aspects, the functionalized chemical structure has the formula:wherein M is a radiopaque or radionuclide metal. In some aspects, M is selected from Bi, Ca, Gd, and Fe. In other aspects, M is selected from Holmium-166, Yttrium-90 and Rhenium- 188.

[0033] In aspects, the functionalized chemical structure has the formula:wherein M is a radiopaque or radionuclide metal. In some aspects, M is selected from Bi, Ca, Gd, and Fe. In other aspects, M is selected from Holmium-166, Yttrium-90 and Rhenium- 188.

[0034] It is noted that metal-chelated oxygen may or may not have a bond to hydrogen, as shown in the structures above. Both are contemplated for any metal-chelated oxygen described herein.

[0035] In aspects, the functionalized chemical structure has the formula:

[0036] For example, in one aspect, the functionalized chemical structure has the formula:

[0037] In aspects, a polyalcohol group may to be used to attach the functionalized chemical structure to the microsphere. For example, a poly alcohol on the surface of the microsphere may be utilized to introduce an alkyl bromide functional group as shown below.The alkyl bromide may then be used to introduce polyamine:The alkyl polyamine may then be used to introduce polycarboxylic acids:

[0038] In aspects, dual drug loading may be achieved as shown below:

[0039] In aspects, an iodinated microsphere may have the structure:

[0040] In aspects a microsphere may be chelated to a metal according to the structure:wherein M can be Gd, Bi, or Fe; or wherein M can be Holmium-166, Yttrium-90, orRhenium-188.

[0041] In aspects, a radio microsphere may have the structure:

[0042] In aspects, a plurality of embolic microspheres may be configured for drug administration and imaging, wherein each embolic microsphere further comprises a therapeutic compound configured to elute from the microsphere.

[0043] In aspects, a pharmaceutical composition may be formulated comprising the embolic microsphere and a pharmaceutically acceptable carrier.

[0044] In aspects, the embolic microspheres may be used to for treating a subject with cancer, the method comprising administering to the subject an effective number of the embolic microspheres. In aspects, computed tomography (CT) imaging may be used to take an image of a tissue of the subject, the tissue having a tumor that has been exposed to the disclosed microspheres. In aspects, the imaging is dual energy CT imaging. In aspects, the embolic microspheres are a first plurality of microspheres comprising a first radiopaque material and wherein the method comprises administering to the subject a second plurality of embolic microspheres, wherein the second plurality of embolic microspheres comprise a second radiopaque material. In aspects, the first plurality of microspheres comprise a first therapeutic agent and the second plurality of microspheres comprise a second therapeutic agent.

[0045] In aspects, the first radiopaque material is a radiopaque metal chelated to the functionalized chemical structure of each microsphere of the first plurality of embolic microspheres. In aspects, the second radiopaque material is iodine.

[0046] In aspects, chelated gadolinium microspheres of the present disclosure may be loaded with single or dual drugs and used for transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). The chelated gadolinium microspheres may be imaged via Computed Tomography (CT), Cone Beam CT (CBCT) or Magnetic Resonance (MR- magnetic embolization) imaging guidance. For dual drug loading, the drug candidates may be carefully selected to exhibit a synergistic effect and / or kill a tumor with different mechanisms of action.

[0047] Gadolinium (Z = 64), heavier than iodine, attenuates x-rays much more effectively for the same molar concentration of the contrast elements. In some aspects, CT image contrast may be increased by fourfold when Gd is used as contrast agent compared with iodine at the same molar concentration and kVp setting (80kVp). Thus, Gd-containing microspheres may provide sufficient contrast enhancement at similar or less concentration ofits iodine counterpart. In addition, these microspheres provide, in conjunction with bismuth or iodine containing microspheres, the ability to image the distribution of multiple drugs in the tissue during and post TACE.

[0048] In aspects, chelated radionuclide metal microspheres of the present disclosure may be used for transarterial radioembolization (TARE) for the treatment of hepatocellular carcinoma (HCC) using radiation. It can also be used to load drug for transarterial radiochemoembolization (TARCE).

[0049] In aspects, functionalized microspheres of the present disclosure may be employed as a boron containing anticancer drug delivery system. For example the microspheres may be used for Boron Neutron Capture Therapy (BNCT). BNCT is a technique that selectively aims to treat tumor cells sparring the normal cells, using boron . The functionalized microspheres of the present disclosure may also be used as a dual therapy: chemo and BNCT.

[0050] In aspects, the functionalized microspheres of the present disclosure may be employed in radioembolization. For example, functionalized microspheres comprising Y-90, Re-188 or Ho-166 may be administered in minimally invasive fashion, similar to TACE, to directly block blood vessels that supply nutrient to a tumor in the liver. These radionuclides emit specifically long range high energy ]3-radiations reaching to the tumor (100 to 1000 Gy) with lethal effect.

[0051] In aspects, the functionalized microspheres of the present disclosure may be functionalized with boron. The boron containing microspheres may have multiple distinct functions. For example, in one aspect they may be used to deliver nonionic anticancer drugs such as capecitabine and similar drugs to a diseased site. In another aspect, the boron containing microspheres may be employed in boron neutron capture therapy (BNCT).

[0052] In aspects, functional groups of the functionalized microparticle such as amines and hydroxyls can be protonated and / or deprotonated depending on the pH of the environment.

[0053] In some aspects, the drugs are ionic with different oncologic mechanisms of action (ie- multi-kinase inhibitors, immunomodulators, and radiation). Thus, the disclosed embolic microsphere platform may be useful to treat liver cancer, such as hepatocellularcarcinoma, or to spatially localize different agents with different geographically-targeted mechanisms of action, calibrated to tumor spatial heterogeneities and specific vulnerabilities.

[0054] The following includes certain aspects of the disclosure.1. A microsphere comprising at least one functionalized chemical structure covalently bonded thereto, the microsphere and functionalized chemical structure having the formula:wherein:represents the microsphere;each R1is independently selected from NH2, NH3, OH. 0, amine, alkoxy, alkyl, and aryl; each R2is independently selected from 0 or OH; and n is greater than or equal to 1.2. The microsphere of aspect 1, wherein the microsphere and functionalized chemical structure have the formula:wherein M is a radiopaque or radionuclide atom; and wherein n is greater than or equal to 1.3 The microsphere of aspect 2, wherein M is selected from Bi, Ca, Gd, and Fe.4. The microsphere of aspect 2, wherein M is selected from Holmium-166, Yttrium-90, and Rhenium-188.5. The microsphere of any one of aspects 1-4, wherein at least one of the R1groups is an amine bonded to an aryl iodide by forming an amide bond.6. The microsphere of aspect 1, wherein the microsphere and functionalized chemical structure have the formula:7. The microsphere of aspect 1, wherein the microsphere and functionalized chemical structure have the formula:8. The microsphere of any one of aspects 1 -7. wherein at least one of the R1groups is independently ionically bonded to a therapeutic compound.9. The microsphere of aspect 8, wherein each R1is independently NHs or 0 .10. A plurality of microspheres for drug administration and imaging, wherein each microsphere of the plurality has a structure according to any one of aspects 1-9, and wherein each microsphere further comprises a therapeutic compound configured to elute from the microsphere.11. A pharmaceutical composition comprising the microsphere of any one of aspects 1-10 and a pharmaceutically acceptable carrier.12. A pharmaceutical composition for use in the treatment of a tumor, the pharmaceutical composition comprising the microspheres of any of one aspects 1-10 or the pharmaceutical composition of aspect 11.13. The pharmaceutical composition for use in the treatment of a tumor of aspect 11, wherein the tumor is a hepatocellular carcinoma.14. A pharmaceutical composition for use in the treatment of a tumor, the treatment comprising exposing the tumor to an effective number of the microspheres of any one of aspects 1-10 or the pharmaceutical composition of aspect 11, and utilizing computed tomography (CT) take an image of the tumor.15. The pharmaceutical composition for use in the treatment of a tumor of aspect 14, wherein the CT imaging is dual energy CT imaging.16. The pharmaceutical composition for use in the treatment of a tumor of any one of aspects 12-15, wherein the microspheres are a first plurality of microspheres comprising a first radiopaque atom and wherein the treatment comprises administering to the subject a second plurality of microspheres, wherein the second plurality of microspheres comprise a second radiopaque atom.17. The pharmaceutical composition of aspect 16, wherein the first plurality of microspheres comprise a first therapeutic agent and the second plurality of microspheres comprise a second therapeutic agent.18. The pharmaceutical composition of any of aspects 16 or 17, wherein the second radiopaque atom is iodine.19. A pharmaceutical composition accordingly to any of aspects 12-18 for use in the treatment of a mammalian tumor.20. A pharmaceutical composition accordingly to any of aspects 12-19 for use in the treatment of a human tumor.

[0055] It shall be noted that the preceding are merely examples of aspects. Other exemplary aspects are apparent from the entirety of the description herein. It will also beunderstood by one of ordinary skill in the art that each of these aspects may be used in various combinations with the other aspects provided herein.

[0056] The following examples further illustrate the disclosure but, of course, should not be construed as in any way limiting its scope.EXAMPLE 1 - Functionalized Embolic Microsphere Platform

[0057] Clinical grade microspheres (Embozene TANDEM) were functionalized with Tris(2-aminoethyl) amine (as shown in Figure 1) and then tnethylenetetramine-N, N, N', N", N"', N'"-hexaacetic acid using aquas phase coupling chemistry to create a functionalized embolic microsphere (as shown in Figure 2). Specifically, turning to Figure 12, 2 grams of Embozene microsphere 1 (250 pm) were suspended in 25 mL of EDC solution (4 mmol, 767 mg) dissolved in 0.1 N MES [2-(N-morpholino)ethanssulfonic acid], 0.9% sodium chloride, pH 4.7; 3 mmol (600 pL) of Tns(2-aminoethyl) amine (225630-lOmL) (density, 0.976 g / mL) was added, dissolved in DMF (2 mL), the reaction mixture was left stirring at RT for 24 hrs (or dissolved in DMA and the reaction mixture was left stirring at RT for 24 hrs). After 24 hrs, the supernatant was removed, and the resulting activated microsphere 2 was washed with IN HC1, IN NaOH, followed by 0. 1 N MES and deionized water until the discoloration of the wash for amine test was observed. Conjugation of the amine was confirmed with positive Kaiser test (shown in Scheme 1). Thus, the functionalized microsphere may function as a platform for multidrug loading capability and imageability as described below.

[0058] Turning now to Figure 13, triethylenetetramine-N,N,N',N'',N''',N'"-hexaacetic acid (4 mmol, 1978 mg) was dissolved in deionized water containing NaOH solution (10 M, 1500 pL, pH ~5) and activated with EDC solution (6 mmol, 1150.2 mg) dissolved in 0. 1 N MES [2-(N-morpholino) ethanssulfonic acid], 0.9% sodium chloride, pH 4.7 (8 mL). The resulting solution was added into a suspension of microsphere 2 in 0.1 MES solution. The reaction mixture was left stirring at 50 °C for 24 hrs. After 24 hrs, the supernatant was removed, and the resulting reactive microsphere 3 was washed with IN NaCl, IN NaOH, 0.9 % saline followed by deionized water. Conjugation of the acid to the amine on the beads was confirmed with negative Kaiser test as shown in Scheme 2 of Figure 13. Thus, the functionalized microsphere may function as a platform for multidrug loading capability and imageability as described below.EXAMPLE 2 - Iodinated Radiopaque Embolic Microspheres

[0059] Functionalized microspheres as prepared in Example 1 were iodinated to produce microspheres as represented in Figure 3A. Turning now to Figure 14, microsphere 3 was washed with 0. 1 N MES and suspended in 5 mL of EDC solution (5 mmol, 960 mg) in 0. 1 N MES [2-(N-morpholino) ethanssulfonic acid], 0.9% sodium chloride, pH 4.7. 2.5 mmol (1302 mg) of (2,3,5-triiodophenyl) methenamine hydrochloride was dissolved in a mixture of 6 mL of DMA and glycerol (1: 1) and added to the reaction mixture and left stirring at 50 °C for 4 hrs. After 4 hrs, the supernatant was removed, and the microspheres were thoroughly washed with deionized water, IN HC1. After neutralization, the microspheres were thoroughly washed with DMA and finally washed with 0. 1 N MES followed by deionized water. Thus, the functionalized microsphere may function as a platform for multidrug loading capability and imageability (Scheme 3). Microsphere integrity and uniform distribution of iodine were analyzed using an upright optical microscope, scanning electron microscopy (Figure 3B), energy dispersive x-ray (Figure 3C) and microCT imaging (Figure 3D). The microsphere 4 had intact spherical shape and darker appearance under optical microscopy but a white visual appearance macroscopically to the naked eye. SEM and energy dispersive X- ray analysis revealed the spherical and intact microsphere, and uniformly distributed radiopaque materials across the entire microsphere, respectively. The iodinated microspheres were radiodense with Hounsfield unit of approximately 2600 ± 600.EXAMPLE 3 - Chelated Bismuth Radiopaque Embolic Microspheres

[0060] Functionalized microspheres as prepared in Example 1 were chelated with bismuth to produce microspheres as represented in Figure 4A (where M3+is bismuth). Turning now to Figure 15, 1 mmol (656.2 mg) of bismuth (III) trifluoromethanesulfonate was dissolved in distilled water and added to microsphere 3 which was washed with IN NaOH and left stirring at 50 °C for 4 hrs. After 4 hrs, the supernatant was removed, and the microspheres thoroughly washed with deionized water, IN HC1, neutralized and finally washed with deionized water. Thus, the functionalized microsphere may function as a platform for multidrug loading capability and imageability (Scheme 4). Microsphere integrity and uniform distribution of bismuth were analyzed using upright optical microscope, Scanning electron microscopy (Figure 4B), energy dispersive x-ray (Figure 4C) and microCTimaging (Figure 4D). The new microsphere had intact spherical shape and darker appearance under optical microscopy but a white visual appearance macroscopically to the naked eye. SEM and energy dispersive X-ray analysis revealed the spherical and intact microsphere, and uniformly distributed radiopaque materials across the entire microsphere, respectively. The microspheres chelated with bismuth were radiodense with Hounsfield unit of approximately 2200 ± 500.

[0061] References

[0062] 1. Lewis, A.L., et al., Bench-to-clinic development of imageable drug-eluting embolization beads: finding the balance. Future Oncology, 2018. 14(26): p. 2741-2760.

[0063] 2. Negussie, A.H., et al., Synthesis and characterization of image-able polyvinyl alcohol microspheres for image-guided chemoembolization. Journal of Materials Science- Materials in Medicine, 2015. 26(6).

[0064] 3. Duran, R., et al., A Novel Inherently Radiopaque Bead for TransarterialEmbolization to Treat Liver Cancer - A Pre-clinical Study. Theranostics, 2016. 6(1): p. 28- 39.

[0065] 4. Song, J.E., et al., Transarterial Radioembolization Versus ConcurrentChemoradiation Therapy for Locally Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis. Int J Radiat Oncol Biol Phys, 2017. 99(2): p. 396-406.

[0066] 5. Ashrafi, K., et al., Characterization of a novel intrinsically radiopaque Drugeluting Bead for image-guided therapy: DC Bead LUMI™. Journal of Controlled Release, 2017. 250: p. 36-47.

[0067] 6. Pan, F., et al., In Vitro Characterization of a Novel Type of RadiopaqueDoxorubicin-Loaded Microsphere. Cardiovasc Intervent Radiol, 2020. 43(4): p. 636-647.

[0068] 7. Levy, E.B., et al., First Human Experience with Directly Image-able IodinatedEmbolization Microbeads. Cardiovascular and Interventional Radiology, 2016. 39(8): p. 1177-1186.

[0069] 8. Negussie, A., Synthesis, characterization, and imaging of radiopaque bismuth beads for image-guided transarterial embolization. Sci. Rep., 2021. 11: p. 533.

[0070] 9. Mikhail, A.S., et al., Mapping Drug Dose Distribution on CT ImagesFollowing Transarterial Chemoembolization with Radiopaque Drug-Eluting Beads in a Rabbit Tumor Model. Radiology, 2018. 289(2): p. 396-404.

[0071] The terms alkyl or alkyl group refer to a monoradical of a straight-chain or branched saturated hydrocarbon. Alkyl groups include straight-chain and branched alkyl groups. Unless otherwise indicated alkyl groups have 1-20 carbon atoms (C1-C20 alkyl groups) and preferred are those that contain 1-10 carbon atoms (Cl -CIO alkyl groups) and more preferred are those that contain 1-6 carbon atoms (C1-C6 alkyl groups) and those that contain 1-3 carbon atoms (C1-C3 alkyl groups) Alkyl groups are optionally substituted with one or more non-hydrogen substituents as described herein. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, branched-pentyl, n- hexyl, branched hexyl, all of which are optionally substituted. Substituted alkyl groups include fully halogenated or semihalogenated alkyl groups, such as alkyl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and / or iodine atoms. Substituted alkyl groups include fully fluorinated or semifluorinated alkyl.

[0072] The term amine refers to an organic compound derived from ammonia by replacement of one or more hydrogen atoms by organic groups. Amines of the present disclosure may include secondary, tertiary or quaternary amines.

[0073] An alkoxy group is an alkyl group (including cycloalkyl), linked to oxygen, a monovalent -O-alkyl group. An aryloxy group is an aryl group, as discussed below, linked to an oxygen, a monovalent -O-aryl. A heteroaryloxy group is a heteroaryl group linked to an oxygen, a monovalent -O-heteroaryl. Alkenoxy, alkynoxy, alicycloxy, heterocycloxy groups are analogously defined. All of such groups are optionally substituted.

[0074] Aryl groups include groups having one or more 5- or 6-member aromatic rings. Aryl groups can contain one, two or three 6-member aromatic rings. Aryl groups can contain two or more fused aromatic rings. Aryl groups can contain two or three fused aromatic rings. Aryl groups are optionally substituted with one or more non-hydrogen substituents. Substituted aryl groups include among others those which are substituted with alkyl or alkenyl groups, which groups in turn can be optionally substituted. Specific aryl groupsinclude phenyl groups, biphenyl groups, and naphthyl groups, all of which are optionally substituted as described herein. Substituted aryl groups include fully halogenated or semihalogenated aryl groups, such as aryl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and / or iodine atoms. Substituted aryl groups include fully fluorinated or semifluorinated aryl groups, such as aryl groups having one or more hydrogen replaced with one or more fluorine atoms.

[0075] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0076] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0077] Preferred aspects of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of those preferred aspectsmay become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A microsphere comprising at least one functionalized chemical structure covalently bonded thereto, the microsphere and functionalized chemical structure having the formula:wherein:CZ represents the microsphere;each R1is independently selected from NH2, NH3, OH. 0, amine, alkoxy, alkyl, and aryl; each R2is independently selected from 0 or OH; and n is greater than or equal to 1.

2. The microsphere of claim 1, wherein the microsphere and functionalized chemical structure have the formula:wherein M is a radiopaque or radionuclide atom; and wherein n is greater than or equal to 1.3 The microsphere of claim 2, wherein M is selected from Bi, Ca, Gd, and Fe.

4. The microsphere of claim 2, wherein M is selected from Holmium-166, Yttrium-90, and Rhenium-188.

5. The microsphere of any one of claims 1-4, wherein at least one of the R1groups is an amine bonded to an aryl iodide by forming an amide bond.

6. The microsphere of claim 1, wherein the microsphere and functionalized chemical structure have the formula:

7. The microsphere of claim 1, wherein the microsphere and functionalized chemical structure have the formula:

8. The microsphere of any one of claims 1-7, wherein at least one of the R1groups is independently ionically bonded to a therapeutic compound.

9. The microsphere of claim 8, wherein each R1is independently NH3+or O“.

10. A plurality of microspheres for drug administration and imaging, wherein each microsphere of the plurality has a structure according to any one of claims 1-9, and wherein each microsphere further comprises a therapeutic compound configured to elute from the microsphere.

11. A pharmaceutical composition comprising the microsphere of any one of claims 1-10 and a pharmaceutically acceptable earner.

12. A pharmaceutical composition for use in the treatment of a tumor, the pharmaceutical composition comprising the microspheres of any of one claims 1-10 or the pharmaceutical composition of claim 11.

13. The pharmaceutical composition for use in the treatment of a tumor of claim 11, wherein the tumor is a hepatocellular carcinoma.

14. A pharmaceutical composition for use in the treatment of a tumor, the treatment comprising exposing the tumor to an effective number of the microspheres of any one of claims 1-10 or the pharmaceutical composition of claim 11, and utilizing computed tomography (CT) take an image of the tumor.

15. The pharmaceutical composition for use in the treatment of a tumor of claim 14, wherein the CT imaging is dual energy CT imaging.

16. The pharmaceutical composition for use in the treatment of a tumor of any one of claims 12-15, wherein the microspheres are a first plurality of microspheres comprising a first radiopaque atom and wherein the treatment comprises administering to the subject a second plurality of microspheres, wherein the second plurality of microspheres comprise a second radiopaque atom.

17. The pharmaceutical composition of claim 16, wherein the first plurality of microspheres comprise a first therapeutic agent and the second plurality of microspheres comprise a second therapeutic agent.

18. The pharmaceutical composition of any of claims 16 or 17, wherein the second radiopaque atom is iodine.

19. A pharmaceutical composition according to any of claims 12-18 for use in the treatment of a mammalian tumor.

20. A pharmaceutical composition according to any of claims 12-19 for use in the treatment of a human tumor.

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